Surgical Immunology: A Historical Reviewo. Role in the Armamentariun of the Surgical Oncologist Charlotte Rose Walker, MD Nashville, Tennessee
Ipmunology is taking its place in multimodality therapy of malignant diseases-currently an adjuvant role. Historical development of this role and definition of terms and principles are herein presented in brief fashion. Introduction This is a most exciting time in the annals and development of the fields of oncology and surgical oncology. The term "oncologist" is applied to the interdisciplinary field of practitioners who have been trained in the multidisciplinary aspects of and team approach to the treatment of neoplasms. The multiple disciplines, in addition to general surgery and surgical oncology, employ multimodality therapy of radiation oncology, medical oncology, and immunology. These methodologies and basic biology studies are proven by time as tQ their relative efficacy, with the exception of tumor immunology and immunotherapy. The latter two, however, have shown an exponential explosion of basic clinical data and experimental observations.
Immunotherapy of Cancer Morton and Wells state that: Cancer surgery is perhaps the most frequently used form of immunotherapy. PresDr. Walker is Assistant Professor of Surgery, Meharry Medical College, Nashville, Tennessee. Requests for reprints should be addressed to Dr. Charlotte Rose Walker, Department of Surgery, Meharry Medical College, Nashville, TN 37208.
ent evidence suggests that the effectiveness of the host's immune defenses is limited because the growing neoplasm seems to be able to evade an immune attack by producing specific and nonspecific immunosuppression in the cancer patient to enhance its growth. The growing neoplasm constantly sheds soluble tumor-associated antigens into the blood and these antigens circulate alone or as antigen-antibody complexes. The extent of the immunosuppression correlates with the stage of the disease and level of tumor burden; it is reversible by removal of the growing neoplasm. Therefore, any therapeutic maneuver that lowers tumor burden may reverse both specific and nonspecific immunosuppression and alter the immune balance in favor of the patient. In this respect, cancer surgery is immunotherapy because it effectively removes the cancer cell mass that produces the immunodepression and allows the patient's immune responses to recover.
Immunotherapy of cancer may also be defined as any immune procedure which adversely affects the growth of an established tumor. Potential or actual malignant cells with differing antigenic determinants are recognized as foreign by an individual's immune system.
Human Immunity A brief review by Moss yields the
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 5, 1979
following capsule historical summary: The first really scientific observation on the peculiar nature of human immunity was made by the famous Greek historian Thucydides (471-400 BC) who witnessed and described the plague which depopulated Athens in 430 BC. His account was that "The sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehension. For no one was ever attacked a second time, or not with a fatal result."2
Such individuals, continues Moss, were later termed immune, meaning those exempt from public service, because recovered plague victims were freed from military service in order to serve as nurses during the great epidemics of the Middle Ages. From such basic observations by Thucydides came the practice of inoculation, which is the deliberate introduction of a small amount of a disease organism to prevent a more serious or fatal infection. This was an ancient practice in Asia. In time, inoculation was supplanted by the safer and more efficient vaccination by Edward Jenner. The following question is raised by Moss in his discussion: "Why do vaccines work, and can this mechanism be
employed to fight cancer?" He con435
tinues to answer: A vaccine contains substances called antigens, chemical molecules which can stimulate a very specific immune response from the body and can react to that response. These antigens are the trademarks of a substance-they identify it, mark its individuality, and make it visible to the immune system."2
Antigens Alexander and Good3 define antigens as those molecular structures having chemical determinant groups capable of stimulating the elaboration of antibodies which have high affinity for combination with the reactant groups of the foreign molecule. They continue that, as the chemical structure of an antigen becomes more unlike the chemical structures of the animal into which it is injected, it becomes more likely to stimulate antibody production. Some antigens are extremely potent, eliciting antibody responses when given in nanogram quantities, while others can be effective as antigens only when given as adjuvants. Antibodies or immunoglobulins, according to Alexander and Good, are specific serum proteins which are synthesized in response to an antigenic stimulus by cells of the gutdependent lymphoid system.
Antibodies A study of our immune systems shows several cells with which we are
primarily concerned because of their interrelated role in surgical immunology. T cells are derived from the thymus and are responsible for the immunologic phenomena of delayed hypersensitivity and allograft rejection. B cells are precursors of cells that make antibody, most specifically, five immunoglobulin classes: Ig G, Ig A, Ig M, Ig E, and Ig D. The B cells are responsible for activation of complement which initiates the inflammatory process and brings about cell lysis. A similar sequence to the coagulation cascade scheme is the classical complement system. There are C1 through C11-nine components that interact in order of their discovery. Other systems of antibodies are opsonins and agglutinins. 436
Immune Response in Cancer Patients Cancer patients show immune responses of two types to their neoplastic antigens: humoral antibodies and cell-mediated immune reactions. Immtline cytotoxicity tests, complement fixation tests, and gel diffusion tests have shown that patients have the ability to form humoral antibodies against a variety of antigenic agents. Studies of cell-mediated immunity have been done in vivo and in vitro. The in vivo studies are assessed by the patient's response in manifestations of delayed cutaneous hypersensitivity to a variety of intradermal antigens to which the general population has been exposed in ubiquitous fashion. Thus, most normal persons (those who are not anergic) react by reason of their previous exposure to PPD, streptokinase, streptodornase, mumnps, and Candida. One answer to the question of whether or not the patient can give a primary immune response is by studying skin allograft survival and sensitization to another antigen; a hapten; or the chem-
ical dinitrochlorobenzene (DNCB), which is a contact allergen. The in vitro studies of cell-mediated immunity employ tests of lymphocyte function by testing their response to foreign tissue antigens or mitogens such as phytohemagglutinin (PHA) or pokeweed mitogen (PWM).
Classification of Treatment As a classification of treatment, immunotherapy is passive or active. Active may be further classified as specific or nonspecific. Passive immunotherapy entails receipt of a reagent that has anti-tumor capability: lymphoid cells, sera, or lymphoid cell products such as transfer factor or immune RNA. Active immunotherapy includes nonspecific reagents which yield an increased immune response. As adjuvants, these agents induce a heightened delayed response to tumor antigens. They may also induce a local reactioni to antigens in the vaccine. BCG, the bacille Calmette Guerin, is employed as several preparations of its fractions: an attenuated strain of Mycobacterium bovis, or MER BCG, which is a nonviable methanol extractable residue of BCG. Mixed bacterial toxins, the prototype of which was
perhaps the mixture of killed (heat) or living streptococcus and Bacillus prodigiosus in a vaccine developed by Dr. Bradford Coley, also are categorized as nonspecific reagents of active immunotherapy. Another example is Corynebacterium parvum, a formalin or heat-killed bacterial agent. A final example is levamisole, a synthetic antihelminthic drug, another nonspecific reagent used in active immunotherapy protocols. Thus, non-specific immunotherapy means that the patient's immune defenses are evoked by adjuvants in order to recall or strengthen a previous immune response. This nonspecificity may augment cellular or humoral immunity and may effect local reactions or stimulate systemic imnmunity. The specific component of active immunotherapy means that the patient's immune defenses are directed against particular antigens such as autologous tumor cell vaccines.
Conclusion Studies of the prognosis and response to immunotherapy have been done utilizing various parameters of immunologic competence. The foregoing account of a historical overview and a simple summary of the response of the host or patient point out the mobilization of immune defenses pursuant to immunologic manipulation in the armamentarium of the surgical on-
cologist. Studies are ongoing to correlate the immunocompetence of the patient and its relation to the development, remission, and/or spread of malignant disease.
Literature Cited 1. Morton DL, Wells SA Jr: Immunobiology and immunotherapy of neoplastic disease. In Sabiston D (ed): Textbook of Surgery. Philadelphia, WB Saunders, 1977, p 602 2. Moss R: Immunology. In Center News, a publication of Memorial Sloan-Kettering Cancer Center 2(11) :4-5, 1 975 3. Alexander JW, Good RA: Immunobiology for Surgeons. Philadelphia, WB Saunders, 1970
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 5, 1979
Ipmunology is taking its place in multimodality therapy of malignant diseases-currently an adjuvant role. Historical development of this role and definition of terms and principles are herein presented in brief fashion. Introduction This is a most exciting time in the annals and development of the fields of oncology and surgical oncology. The term "oncologist" is applied to the interdisciplinary field of practitioners who have been trained in the multidisciplinary aspects of and team approach to the treatment of neoplasms. The multiple disciplines, in addition to general surgery and surgical oncology, employ multimodality therapy of radiation oncology, medical oncology, and immunology. These methodologies and basic biology studies are proven by time as tQ their relative efficacy, with the exception of tumor immunology and immunotherapy. The latter two, however, have shown an exponential explosion of basic clinical data and experimental observations.
Immunotherapy of Cancer Morton and Wells state that: Cancer surgery is perhaps the most frequently used form of immunotherapy. PresDr. Walker is Assistant Professor of Surgery, Meharry Medical College, Nashville, Tennessee. Requests for reprints should be addressed to Dr. Charlotte Rose Walker, Department of Surgery, Meharry Medical College, Nashville, TN 37208.
ent evidence suggests that the effectiveness of the host's immune defenses is limited because the growing neoplasm seems to be able to evade an immune attack by producing specific and nonspecific immunosuppression in the cancer patient to enhance its growth. The growing neoplasm constantly sheds soluble tumor-associated antigens into the blood and these antigens circulate alone or as antigen-antibody complexes. The extent of the immunosuppression correlates with the stage of the disease and level of tumor burden; it is reversible by removal of the growing neoplasm. Therefore, any therapeutic maneuver that lowers tumor burden may reverse both specific and nonspecific immunosuppression and alter the immune balance in favor of the patient. In this respect, cancer surgery is immunotherapy because it effectively removes the cancer cell mass that produces the immunodepression and allows the patient's immune responses to recover.
Immunotherapy of cancer may also be defined as any immune procedure which adversely affects the growth of an established tumor. Potential or actual malignant cells with differing antigenic determinants are recognized as foreign by an individual's immune system.
Human Immunity A brief review by Moss yields the
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 5, 1979
following capsule historical summary: The first really scientific observation on the peculiar nature of human immunity was made by the famous Greek historian Thucydides (471-400 BC) who witnessed and described the plague which depopulated Athens in 430 BC. His account was that "The sick and the dying were tended by the pitying care of those who had recovered, because they knew the course of the disease and were themselves free from apprehension. For no one was ever attacked a second time, or not with a fatal result."2
Such individuals, continues Moss, were later termed immune, meaning those exempt from public service, because recovered plague victims were freed from military service in order to serve as nurses during the great epidemics of the Middle Ages. From such basic observations by Thucydides came the practice of inoculation, which is the deliberate introduction of a small amount of a disease organism to prevent a more serious or fatal infection. This was an ancient practice in Asia. In time, inoculation was supplanted by the safer and more efficient vaccination by Edward Jenner. The following question is raised by Moss in his discussion: "Why do vaccines work, and can this mechanism be
employed to fight cancer?" He con435
tinues to answer: A vaccine contains substances called antigens, chemical molecules which can stimulate a very specific immune response from the body and can react to that response. These antigens are the trademarks of a substance-they identify it, mark its individuality, and make it visible to the immune system."2
Antigens Alexander and Good3 define antigens as those molecular structures having chemical determinant groups capable of stimulating the elaboration of antibodies which have high affinity for combination with the reactant groups of the foreign molecule. They continue that, as the chemical structure of an antigen becomes more unlike the chemical structures of the animal into which it is injected, it becomes more likely to stimulate antibody production. Some antigens are extremely potent, eliciting antibody responses when given in nanogram quantities, while others can be effective as antigens only when given as adjuvants. Antibodies or immunoglobulins, according to Alexander and Good, are specific serum proteins which are synthesized in response to an antigenic stimulus by cells of the gutdependent lymphoid system.
Antibodies A study of our immune systems shows several cells with which we are
primarily concerned because of their interrelated role in surgical immunology. T cells are derived from the thymus and are responsible for the immunologic phenomena of delayed hypersensitivity and allograft rejection. B cells are precursors of cells that make antibody, most specifically, five immunoglobulin classes: Ig G, Ig A, Ig M, Ig E, and Ig D. The B cells are responsible for activation of complement which initiates the inflammatory process and brings about cell lysis. A similar sequence to the coagulation cascade scheme is the classical complement system. There are C1 through C11-nine components that interact in order of their discovery. Other systems of antibodies are opsonins and agglutinins. 436
Immune Response in Cancer Patients Cancer patients show immune responses of two types to their neoplastic antigens: humoral antibodies and cell-mediated immune reactions. Immtline cytotoxicity tests, complement fixation tests, and gel diffusion tests have shown that patients have the ability to form humoral antibodies against a variety of antigenic agents. Studies of cell-mediated immunity have been done in vivo and in vitro. The in vivo studies are assessed by the patient's response in manifestations of delayed cutaneous hypersensitivity to a variety of intradermal antigens to which the general population has been exposed in ubiquitous fashion. Thus, most normal persons (those who are not anergic) react by reason of their previous exposure to PPD, streptokinase, streptodornase, mumnps, and Candida. One answer to the question of whether or not the patient can give a primary immune response is by studying skin allograft survival and sensitization to another antigen; a hapten; or the chem-
ical dinitrochlorobenzene (DNCB), which is a contact allergen. The in vitro studies of cell-mediated immunity employ tests of lymphocyte function by testing their response to foreign tissue antigens or mitogens such as phytohemagglutinin (PHA) or pokeweed mitogen (PWM).
Classification of Treatment As a classification of treatment, immunotherapy is passive or active. Active may be further classified as specific or nonspecific. Passive immunotherapy entails receipt of a reagent that has anti-tumor capability: lymphoid cells, sera, or lymphoid cell products such as transfer factor or immune RNA. Active immunotherapy includes nonspecific reagents which yield an increased immune response. As adjuvants, these agents induce a heightened delayed response to tumor antigens. They may also induce a local reactioni to antigens in the vaccine. BCG, the bacille Calmette Guerin, is employed as several preparations of its fractions: an attenuated strain of Mycobacterium bovis, or MER BCG, which is a nonviable methanol extractable residue of BCG. Mixed bacterial toxins, the prototype of which was
perhaps the mixture of killed (heat) or living streptococcus and Bacillus prodigiosus in a vaccine developed by Dr. Bradford Coley, also are categorized as nonspecific reagents of active immunotherapy. Another example is Corynebacterium parvum, a formalin or heat-killed bacterial agent. A final example is levamisole, a synthetic antihelminthic drug, another nonspecific reagent used in active immunotherapy protocols. Thus, non-specific immunotherapy means that the patient's immune defenses are evoked by adjuvants in order to recall or strengthen a previous immune response. This nonspecificity may augment cellular or humoral immunity and may effect local reactions or stimulate systemic imnmunity. The specific component of active immunotherapy means that the patient's immune defenses are directed against particular antigens such as autologous tumor cell vaccines.
Conclusion Studies of the prognosis and response to immunotherapy have been done utilizing various parameters of immunologic competence. The foregoing account of a historical overview and a simple summary of the response of the host or patient point out the mobilization of immune defenses pursuant to immunologic manipulation in the armamentarium of the surgical on-
cologist. Studies are ongoing to correlate the immunocompetence of the patient and its relation to the development, remission, and/or spread of malignant disease.
Literature Cited 1. Morton DL, Wells SA Jr: Immunobiology and immunotherapy of neoplastic disease. In Sabiston D (ed): Textbook of Surgery. Philadelphia, WB Saunders, 1977, p 602 2. Moss R: Immunology. In Center News, a publication of Memorial Sloan-Kettering Cancer Center 2(11) :4-5, 1 975 3. Alexander JW, Good RA: Immunobiology for Surgeons. Philadelphia, WB Saunders, 1970
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 5, 1979
